U.S. patent application number 14/351606 was filed with the patent office on 2014-09-04 for anti-tumoral compound and relative production process.
This patent application is currently assigned to Seventeen SRL. The applicant listed for this patent is Giulia Di Capua. Invention is credited to Giulia Di Capua.
Application Number | 20140248209 14/351606 |
Document ID | / |
Family ID | 45496226 |
Filed Date | 2014-09-04 |
United States Patent
Application |
20140248209 |
Kind Code |
A1 |
Di Capua; Giulia |
September 4, 2014 |
ANTI-TUMORAL COMPOUND AND RELATIVE PRODUCTION PROCESS
Abstract
An anti-tumoral compound for the localized treatment of
neoplastic pathologies of malignant kind that cannot be surgically
removed or with a high risk of local recurrence, includes: a
bicomponent injectable biologic glue; an antineoplastic substance;
and an epinephrine-based solution. The compound may be used as an
independent therapeutic treatment, as it allows to treat tumoral
masses that are not surgically removable, or as a therapeutic
treatment complementary to surgical removal or to known ablative
techniques (laser, radiofrequency, microwaves, etc.) for a
maximization of the efficiency of therapies reducing the risk of
neoplastic relapses in the original surgical site. A process for
the production of the antitumor compound is also described.
Inventors: |
Di Capua; Giulia; (Napoli,
IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Di Capua; Giulia |
Napoli |
|
IT |
|
|
Assignee: |
Seventeen SRL
Roma
IT
|
Family ID: |
45496226 |
Appl. No.: |
14/351606 |
Filed: |
October 21, 2011 |
PCT Filed: |
October 21, 2011 |
PCT NO: |
PCT/IT2011/000354 |
371 Date: |
April 14, 2014 |
Current U.S.
Class: |
424/1.11 ;
514/653 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61K 51/1251 20130101; A61K 51/1213 20130101; A61K 45/06 20130101;
A61K 47/10 20130101; A61K 9/06 20130101; A61P 35/00 20180101; A61K
31/137 20130101; A61K 47/42 20130101; A61K 31/137 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/1.11 ;
514/653 |
International
Class: |
A61K 51/12 20060101
A61K051/12; A61K 47/10 20060101 A61K047/10; A61K 47/42 20060101
A61K047/42; A61K 31/137 20060101 A61K031/137; A61K 45/06 20060101
A61K045/06 |
Claims
1. An anti-tumoral compound, characterized in that it comprises: an
injectable biologic glue consisting of two distinct chemical mix;
an antineoplastic substance; an epinephrine-based solution, wherein
said injectable biologic glue is arranged for solidifying, thus
keeping the antineoplastic substance in loco in cooperation with
the vasoconstriction effect induced by epinephrine.
2. An anti-tumoral compound according to claim 1, characterized in
that the injectable biologic glue is a haemostatic gel.
3. An anti-tumoral compound according to claim 2, characterized in
that said haemostatic gel comprises a fibrinogen and
aprotinin-based mix, and a trombine and calcium chloride-based
mix.
4. An anti-tumoral compound according to claim 1, characterized in
that the injectable biologic glue is a hydrogel.
5. An anti-tumoral compound according to claim 4, characterized in
that said hydrogel comprises a synthetic polyethylene glycols and
diluted hydrochloric acid-based mix, and a synthetic polyethylene
glycols and sodium phosphate/sodium carbonate-based mix.
6. An anti-tumoral compound according to claim 1, characterized in
that said injectable biologic glue is arranged for being given to
patients by means of a double lumen catheter.
7. An anti-tumoral compound according to claim 1, characterized in
that the antineoplastic substance comprises a solution of
biocompatible microspheres with radiotherapy action as a
therapeutic agent.
8. An anti-tumoral compound according to claim 7, characterized in
that said biocompatible microspheres are labelled with a
radioactive isotope for therapeutic use having a high energy
electrons emission and with a tissue penetration capacity of >5
mm, equal to 500-625 cellular layers.
9. An anti-tumoral compound according to claim 8, characterized in
that said isotope contained inside said biocompatible microspheres
is the yttrium radioactive isotope (90Y).
10. An anti-tumoral compound according to claim 1, characterized in
that said antineoplastic substance comprises a compound with
chemotherapy action.
11. A process for the production of a compound for antitumor use,
characterized in that it comprises: a preparation phase of a
chemical fibrinogen and aprotinin-based injectable compound; a
preparation phase of a chemical trombine and calcium chloride-based
injectable compound; a phase of pre-dosing of said chemical
compounds, inside special disposable syringes, and the subsequent
low temperature storage of the same; a warming phase of said
compounds, when they are to be used, up to the temperature of
37.degree. C.; a first phase of adding said compounds carried out
by means of a solution of biocompatible microspheres, labelled with
a high energy isotope for therapeutic use, like the yttrium
radioactive isotope (.sup.90Y); a second phase of adding said
compounds, carried out by means of an epinephrine-based solution;
an administration phase of equivalent doses of said compounds,
determining the localized formation of a haemostatic gel comprising
above listed adding substances, carried out by means of a special
coaxial catheter with double lumen.
12. A process for the production of a compound for antitumor use,
characterized in that it comprises: a preparation phase of a
chemical injectable compound consisting of a synthetic polyethylene
glycol and of a diluted solution of hydrochloric acid; a
preparation phase of a chemical injectable compound consisting of a
synthetic polyethylene glycol and of a solution of sodium
phosphate/sodium carbonate; a pre-dosing phase of said chemical
compounds inside special disposable syringes, and the subsequent
low temperature storage of the same; a warming phase of said
compounds at the moment of use up to the temperature of 37.degree.
C.; a first phase of adding said compounds, carried out by means of
a solution of biocompatible microspheres, labelled with a high
energy isotope for therapeutic use, like the yttrium radioactive
isotope (.sup.90Y); a second phase of adding said compounds,
carried out by means of an epinephrine-based solution; an
administration phase of equivalent doses of said compounds,
determining the localized formation of a hydrogel comprising above
mentioned adding substances, carried out by means of a special
coaxial catheter with double lumen.
13. A process according to claim 11, characterized in that above
mentioned phase of adding the compounds, carried out with a
solution of biocompatible microspheres labelled with a high energy
isotope for therapeutic use, like the yttrium radioactive isotope
(90Y), is replaced by a phase of adding chemotherapy drugs.
14. A process according to claim 12, characterized in that above
mentioned phase of adding the compounds, carried out with a
solution of biocompatible microspheres labelled with a high energy
isotope for therapeutic use, like the yttrium radioactive isotope
(90Y), is replaced by a phase of adding chemotherapy drugs.
Description
[0001] The present invention relates to the field of therapeutic
drugs and medicines for antitumor treatments.
[0002] More in detail, the present invention concerns An
anti-tumoral compound for the localized treatment of neoplastic
pathologies of malignant kind that cannot be excised by surgery, or
with a high risk of local recurrence.
[0003] It is well known that in presence of neoplastic pathologies
of malignant kind like, e.g., hepatocellular carcinoma, colorectal
cancer or breast cancer, the removal of the tumoral mass is the
only therapeutic treatment that guarantees the long term survival
of the patient.
[0004] It is furthermore known that, at the light of the present
medical knowledge, not all neoplastic pathologies of malignant kind
may be removed by surgery, as said therapeutic method is tightly
depending on the patient's clinical condition, on the localization
of the neoplasias and on the morphologic features of the tumoral
mass to be removed.
[0005] The removal of a neoplastic mass by surgical resection
cannot be performed in the following cases: [0006] if in the
patient's body there is a non neoplastic pathology (comorbidity)
involving the organ attacked by the tumoral mass, or the anatomic
region comprising the same; [0007] if the removal of the tumoral
mass determines the alteration of the functionality of the treated
organ; [0008] if the removal of the tumoral mass determines
aesthetic or functional modifications such as to permanently change
the lifestyle of the patient.
[0009] Furthermore, the surgical removal of a tumoral mass can not
be performed without the certainty of obtaining a resection margin
of healthy tissue of at least one centimetre from the infiltration
limit of the tumoral cells, as it has been widely shown that
resection margins less than one centimetre favour the recurrence of
neoplastic pathologies of malignant kind in the original surgical
site.
[0010] It is known that therapeutic methods alternative to surgical
resection of a tumoral mass usually comprise: [0011] chemotherapy
or radiotherapy treatments, systemic and/or locoregional; [0012]
intra-arterial treatments like, e.g., chemoembolization,
chemoperfusion or radioembolization; [0013] localized ablative
treatments, obtained by means of quick freezing (cryoablation),
chemical desiccation (alcohol ablation), or necrosis of tumor cells
induced by hyperthermia (ablation by means of laser, microwaves,
radio frequency, etc.).
[0014] It is further known that said methods have important and
numerous limits or side effects, as: [0015] the high toxicity of
the antineoplastic substances used in the treatments like
chemotherapy and radiotherapy makes a long term application of said
therapies impossible; [0016] the quick freezing of the tumoral
tissues, or the necrosis induced by hypothermia thereof, causes
breaks and bleedings in the cell structure of the treated organs;
[0017] the desiccation of the tumoral tissues, obtained by the
localized injection of alcohol, determines an incomplete necrosis
of the same due to a non uniform distribution of said substance
through the tissues.
[0018] Furthermore, none of said therapies proves to be radical for
the purpose of allowing a long term survival of the patient.
[0019] In the pharmaceutical field, the method consisting in the
inclusion of one or more active principles in a viscous material,
functioning as a carrier of the same, for obtaining medical
compounds allowing the localized treatment of different
pathologies, is well known.
[0020] Among the many typologies of compounds that may be commonly
obtained with said method, those with anti-inflammatory,
antimicrobial, antihemorrhagic, dermoregenerating, analgesic,
disinfectant and other action will be reported as an example.
[0021] Therefore, it is the aim of the present invention to obtain
a compound for antitumor use that may be applied for the local
treatment of neoplastic pathologies of malignant kind that cannot
be surgically treated or showing a high risk of local recurrence by
the inclusion, in a viscous material functioning as a carrier, of a
substance having appropriate neoplastic capacities and functioning
as a therapeutic agent.
[0022] It is furthermore the aim of the present invention to
overcome some of the problems and of the limits deriving from the
use of therapeutic methods commonly used for the treatment of
neoplastic pathologies of malignant kind which cannot be treated
surgically, or having a high risk of local recurrence.
[0023] The aim set forth is reached by means of an anti-tumoral
compound, characterized in that it comprises: [0024] an injectable
biological glue consisting of two distinct chemical mix; [0025] an
antineoplastic substance; [0026] an epinephrine-based solution;
wherein said injectable biological glue is arranged for
solidifying, keeping the antineoplastic substance in loco in
cooperation with the vasoconstriction effect induced by
epinephrine.
[0027] According to a preferred embodiment of the present
invention, the injectable biological glue is a haemostatic gel, or
a hydrogel.
[0028] According to a further embodiment, the compound according to
the present invention may comprise an antineoplastic substance with
radiotherapy or chemotherapy effect.
[0029] A process for the production of said anti-tumoral compound
is also the object of the present invention.
[0030] The compound according to the present invention has many and
important advantages: [0031] it may be given at an intra-tumoral
level, for the purpose of determining the complete necrosis of the
tumoral tissues around the inoculation area, thus allowing the
treatment of tumoral masses of malignant kind that cannot be
surgically removed; [0032] it may be applied as a filling material
of surgical wounds deriving from a surgical resection, or from
ablative treatments, of tumoral masses of malignant kind, for the
purpose of determining the complete necrosis of possible residual
tumoral cells localized along the edges of said wounds; [0033] it
determines a greater efficiency of antineoplastic substances,
producing a favourable increase of the administration period and of
the dosage of said substances at a local level, due to the
concentration of the same inside the treated tumoral masses, or
inside said surgical wounds deriving from surgical removal, or from
ablative treatments, of the same; [0034] it prevents the free
diffusion of said antineoplastic substances in the body of the
patient, consequently limiting the systemic exposure to the toxic
components of the same; [0035] it allows overcoming of the side
effects deriving from the application of the therapeutic methods
substitute for the surgical resection of the tumoral masses of
malignant kind; [0036] besides, the inclusion of neoplastic
substances into a material having viscous structure limits the
exposure of the medical staff to the toxic components of said
antineoplastic substances when the drug is given to the
patient.
[0037] The anti-tumoral compound according to the present invention
is based, as said before, on the principle if including a substance
with suitable antineoplastic capacities into a special material
with a viscous structure, arranged for functioning as a carrier for
said substance.
[0038] Special biocompatible microspheres have been labelled with a
radioactive high energy isotope for therapeutic use, then including
the radiolabelled microspheres into a quick solidification
haemostatic gel, thus obtaining a compound for antitumor action
that may be directly inoculable inside tumoral masses that cannot
be surgically treated, or that may be applied as a filling material
in surgical wounds deriving from surgical resection of said tumoral
masses.
[0039] Actually, histologic examinations have shown that said
compound induces a favourable necrosis of the neoplastic cells in
the area corresponding to inoculation into the tumoral mass of
interest, or near the application area in the wound deriving from
surgical resection of said tumoral mass. The necrosis of the
tumoral cells of interest is induced by means of an appropriate
internal radiotherapy with electrons (IRE), determined by the
localized emission of radioactive particles by said radiolabelled
microspheres.
[0040] Laboratory examinations, carried out in a gamma camera and
with PET/CT, have surprisingly shown that the compound spreads in
an almost homogeneous manner inside the tumoral mass into which it
has been inoculated, or inside the surgical wound onto which it has
been applied, due to the viscous structure of the haemostatic gel
forming the matrix thereof, and that such homogeneous diffusion is
highly functional to the necrosis of the neoplastic cells localized
in such areas.
[0041] The same examinations have also surprisingly shown that, if
a haemostatic gel with a sufficient solidification speed is used as
a carrier of said radiolabelled microspheres, the possible
dispersion of said microspheres in the patient's body--potentially
deriving from factors like gravity, their diffusion in the blood
and/or lymphatic vessels, the presence of serosanguineous
collections and other--is strongly limited, consequently avoiding
any possible side effect deriving from possible dispersion of
radioactive material in the patient himself.
[0042] Finally, further laboratory examinations have shown that the
dispersion of the radiolabelled microspheres in the patient's body
may be further limited including a substance in the compound
arranged for determining a temporary vasoconstriction of the
tissues surrounding the inoculation or application point of the
same.
[0043] According to the present invention, and in a not restrictive
exemplification, an anti-tumoral compound for local use according
to the present invention mainly consists of: [0044] a quick
solidification, bicomponent haemostatic gel resulting from the
localized injection of two distinct chemical compounds, dosed in
adequate ratio of quantity, one of which is fibrinogen and
aprotinin-based, and the other one of which is trombine and calcium
chloride-based; [0045] a solution of biocompatible microspheres,
arranged for being included in the chemical solutions forming above
mentioned haemostatic gel, labelled with a high energy radioactive
isotope for therapeutic use, like e.g. the radioactive yttrium
(.sup.90Y), such as to determine the necrosis of the tumoral
tissues around the inoculation or application area of the
anti-tumoral compound; [0046] an epinephrine-based solution, also
arranged for being included in the chemical solutions forming said
haemostatic gel, such as to determine a temporary vasoconstriction
effect to the tissues around the inoculation or application area of
said anti-tumoral compound.
[0047] According to the present invention, above described
anti-tumoral compound is arranged for being directly inoculated
into tumoral masses of malignant kind that cannot be surgically
treated, for determining the complete necrosis of the neoplastic
cells that are near the inoculation point thereof.
[0048] It is also arranged for being applied as a filling material
in surgical wounds deriving from surgical resection, or from
ablative treatments, of tumoral masses of malignant kind, for
determining the complete necrosis of possible residual neoplastic
cells along the edges of the wounds, so that said edges are
surrounded by at least one centimetre of healthy tissue thus
reducing the risk of a possible recurrence of the neoplasia in the
original site.
[0049] Said anti-tumoral compound induces the complete necrosis of
the neoplastic cells near its inoculation or application point by
means of an adequate internal radiotherapy with electrons (IRE)
determined by the localized emission of radioactive particles by
the radiolabelled microspheres comprised in the haemostatic gel
forming the matrix thereof. Moreover, the complete necrosis of the
neoplastic cells is favoured by the homogeneous distribution of the
compound inside the tumoral mass into which it is inoculated or
inside the surgical wound onto which it is applied, which is made
possible due to the viscosity of the haemostatic gel forming the
matrix thereof.
[0050] Evidence of the homogeneous distribution of the compound in
cavity is given in enclosed FIGS. 1 and 2 wherein, by a
gamma-camera in front and back projection, the distribution of 1
mCi (37 MBq) of microspheres is shown, said microspheres being
radiolabelled with the radioactive yttrium isotope (.sup.90Y) and
comprised in a quick solidification bicomponent haemostatic gel,
inside a 2.5 ml syringe barrel.
[0051] FIGS. 3 and 4 show--respectively by means of PET/CT and
CT--the distribution of 340-370 microspheres MBq, radiolabelled
with the radioactive yttrium isotope (.sup.90Y) and comprised in a
quick solidification, bicomponent haemostatic gel, inside 5 ml
volume plastic spheres.
[0052] Such figures also show that the anti-tumoral compound does
not reveal any dissociation between the solutions and the
solidified gel, and that said gel does not reveal alterations of
its distribution and of its solidification near the cavity of
interest.
[0053] The quick solidification of the haemostatic gel, forming the
matrix of the anti-tumoral compound, determines the confinement of
the radiolabelled microspheres inside the inoculation or
application site of said compound, advantageously producing a
prolongation of its administration time and a consequent increase
of its local dosage, deriving from the strong concentration of said
microspheres inside each single tumoral mass, or of each single
surgery wound treated.
[0054] The quick solidification of said haemostatic gel also limits
the dispersion of the radiolabelled microspheres in the patient's
body, potentially caused by factors like the gravity, the diffusion
in blood and lymphatic vessels, the presence of serosanguineous
collections and other, consequently avoiding the setting in of
common side effects due to the dispersion of radioactive material
in the patient himself.
[0055] Said haemostatic gel is obtained by the local injection of a
couple of distinct chemical solutions, according to appropriate
ratios, one of which fibrinogen and aprotinin-based, with a dosage
of 1 ml, and the other one trombine and calcium chloride-based,
with a dosage of 0.75 ml.
[0056] The injection of the two chemical solutions forming said
haemostatic gel by means of a coaxial catheter with double lumen,
e.g. of the kind disclosed in patent application MI2009A000969 of 3
Jun. 2009.
[0057] Said gel comprises a solution of biocompatible microspheres
labelled with a radioactive isotope for therapeutic use,
characterized in the emission of high energy electrons and with a
penetration power in the tissue>5 mm, equal to 500-625 cellular
layers, and preferably represented by the yttrium radioactive
isotope (.sup.90Y).
[0058] With a dosage of 0.25 ml, said solution allows to include
inside said haemostatic gel a quantity of biocompatible
microspheres equal to 30-60.times.10.sup.6 with a diameter
comprised between 20 and 60 micron and labelled with the
radioactive yttrium isotope (.sup.90Y), having an average life of
64.1 hours and a tissue penetration coefficient of 11 mm, with an
average penetration of the same of 2.5 mm, such as to determine the
complete necrosis of the cancer tissues surrounding the inoculation
or application area of the examined anti-tumoral compound.
[0059] Said microspheres, which are unassimilable by the human
body, release 94% of the radioactivity of the yttrium isotope
(.sup.90Y) contained therein, in a time period superior to the
average physical and biological life of said isotope, evaluated in
10-13 days from the moment of inoculation or application of said
anti-tumoral compound.
[0060] FIG. 5 shows in a graph the results of the measurements,
done through a gamma camera and PEC/CT, of the absorption
percentage of the radioactivity released by said microspheres in
contiguous shells with dimensions of 1 mm, near cavities of
different volumes A, B, C, respectively equal to 0.5 ml, 4.2 ml and
11.5 ml.
[0061] FIG. 6 shows in a graph the results of the measurements of
the activity percentage of the yttrium radioactive isotope
(.sup.90Y), according to its distance from the centre of said
reference cavities.
[0062] The data shown in the graphs in FIGS. 7 and 8 have been
processed from the activity values of the yttrium isotope
(.sup.90Y), released for each reference cavity, and said figures
respectively show: [0063] the entity of radiation dosage (Gy/MBq)
absorbed per unity, in adjoining shells of cavities of different
dimensions, with reference volumes respectively equal to 0.5 ml,
4.2 ml and 11.5 ml; [0064] entities of radiation dosage (Gy)
absorbed in a whole, in adjoining shells of cavities of different
dimensions, with reference volumes respectively equal to 0.5 ml,
4.2 m and 11.5 ml.
[0065] Following table 1, on the other hand, reports the results of
the measurements of the radiation dosage absorbed by wounds of
different dimension, with the reference radius respectively equal
to 0.5 cm, 1 cm and 1.5 cm.
TABLE-US-00001 TABLE 1 Act. Act. Act. Volume Radius 185 Volume
Radius 370 Volume Radius 1110 0.5 ml 0.5 cm MBq 4.2 ml 1 cm MBq
14.1 ml 1.5 cm MBq cm Gy/MBq Gy cm Gy/MBq Gy cm Gy/MBq Gy 0.5 62.9
11640 1.0 10.1 3732.3 1.5 3.46 3843.2 0.6 35.0 6467 1.1 6.7 2488.2
1.6 1.15 1281.1 0.7 14.0 2587 1.2 2.2 829.4 1.7 0.81 896.7 0.8 5.6
1035 1.3 1.0 373.2 1.8 0.35 384.3 0.9 2.1 388 1.4 0.6 207.4 1.9
0.12 128.1 1.0 0.559 103 1.5 0.112 41.5 2.0 0.06 64.1 1.2 0.070 13
1.6 0.004 1.7 2.1 0.0092 10.2 1.5 0.0002 0.04 1.7 0.001 0.4 2.3
0.0012 1.3
[0066] The results of the measurements, and of the processing
deriving therefrom, confirm the strong concentration of the
radiotherapy action of the radiolabelled microspheres near the
inoculation or application point of the examined anti-tumoral
compound.
[0067] Besides, the results confirm the limited dispersion of
radioactive elements in the areas around the inoculation or
application point of said compound, and consequently their limited
dispersion in the patient's body.
[0068] As an alternative to above mentioned biocompatible
microspheres, common antineoplastic substances with chemotherapy
action may be comprised inside said haemostatic gel forming the
matrix of said anti-tumoral compound.
[0069] Furthermore, an epinephrine solution is included inside said
haemostatic gel, with a dosage equal to 0.1 ml/mg, arranged for
determining a temporary vasoconstriction of the tissues around the
inoculation or application area of the compound.
[0070] Said solution determines an advantageous increase of the
haemostatic effect already given by the gel forming the matrix of
said compound and, strongly reducing the bleeding of the tissues
treated, it further limits the dispersion of the antineoplastic
substances in the patient's body and thus avoids the arising of
common side effects deriving from the systemic exposure to the
toxic components of the same.
[0071] The particular features of the anti-tumoral compound above
described, like the highly localized administration and the limited
dispersion of the antineoplastic substances contained therein,
allow an advantageous use of said compound in the field of the
therapeutic treatment of tumoral masses localized in the area of
the head and in the brain tissues, in the area of the neck, of the
chest cavity, of the abdominal cavity and in the area of the
retroperitoneal space, in the area of the pelvis as well as in the
bones and in the soft tissues in general.
[0072] Said features also allow the use of said compound as an
independent therapeutic treatment, suitable for allowing the
treatment of tumoral masses that cannot be surgically removed, or
as a therapeutic treatment complementary to surgical resection, or
to alternative surgical techniques, suitable for maximizing the
efficiency of those therapies and reducing the risk of neoplastic
recurrences in the original site.
[0073] Best results have been obtained, with respect to similar
substances, with the use of TISSUCOL (BAXTER) or Beriplast P
(Nycomed), as a biological glue of SIR (SIRTeX) spheres as
biocompatible microsphere solution; and of epinephrine (adrenaline)
belonging to the adrenergic activity catecholamines of A and B
type, as a local vasoconstrictor agent on the smooth muscles.
[0074] Best results have been obtained also with the use of the
biological glue Coseal (BAXTER), a surgical sealant resulting from
the localized injection of two different synthetic polyethylene
glycols (PEGs), of a diluted solution of hydrochloric acid and of a
solution of sodium phosphate/sodium carbonate.
[0075] During administration, said polyethylene glycols and said
solutions form a hydrogel that adheres to the tissues and
covalently binds itself to the same.
[0076] The pharmacologic behaviour of the anti-tumoral compound
according to the present invention has been examined in different
species, making use of animals with spontaneous or implanted
neoplasias.
[0077] The results of said studies have shown--in imaging
mode--that following to the administration of the compound in the
wound, no loss of radiolabelled microspheres occurs in the tissues
around the area of its inoculation or application.
[0078] By means of autoradiography it has been proved, in
particular, that the dose injected in the tested animals remains
active inside the solidified gel until 13 days after its
injection.
[0079] Histological examination in a number of pigs has shown the
necrosis of all neoplastic cells comprised in the area of
administration of the anti-tumoral compound and said area varies
between 0.6 and 3.2 mm.
[0080] The dose given to the animals has been considered
tumoricidal for wounds between 3 and 22 cc, and no radioactivity
has been found in the blood of the same.
[0081] Besides, different dosages of yttrium radioactive isotope
(.sup.90Y) have been evaluated, according to the volume of the
residual surgical cavity to be filled up or to the dimensions of
the wound to be treated, as appropriately summed up in following
Table 2.
TABLE-US-00002 TABLE 2 Volume of the Activity of the Volume of
remaining cavity or .sup.90Y isotope injected medicine of the wound
(cc) (MBq) (ml) 1 259-370 (7-10 mCi) 3 3 444-555 (12-15 mCi) 4 5
592-740 (16-20 mCi) 6 10 1110-1480 (30-40 mCi) 12 20 2220-2960
(60-80 mCi) 24 >20 3000 24
[0082] The precondition for the dosimetric evaluation is that the
yttrium radioactive isotope (.sup.90Y) is homogeneously distributed
inside the residual surgical cavity and inside the solidified gel
forming the matrix of said compound, obtained through the
co-injection of TISSUCOL (BAXTER), or Beriplast P (Nycomed), and
epinephrine.
[0083] The different components of the haemostatic gel forming the
matrix of the anti-tumoral compound have been given through a 2.5
ml syringe by means of a slow infusion carried out through a
special coaxial catheter with double lumen.
[0084] The ratio between the fibrinogen-aprotinin solution, the
trombine-calcium chloride solution and the microsphere SIR solution
was respectively of 1 ml:0.75 ml:0.25 ml.
[0085] In this preparation, the activity of the yttrium radioactive
isotope (.sup.90Y) has been of 22 MBq (0.6 mCi).
[0086] The exposure of the staff to the components of the compound
has been evaluated by means of a dosimetric thermoluminescence
detector (TDL), because the preparation and the administration
procedure of the compound must be considered as potentially
dangerous.
[0087] Such exposure has been estimated supposing to manage a 3 GBq
device with a time for preparing the dose of 30 minutes (for
technical staff) and suggesting an average dose of 2 GBq in the
patients and a time for the injection of the dose of 20 minutes
(for medical staff).
[0088] During work, the detector has been placed near the pelvis,
on the collar of the T-shirt and on the fingers.
[0089] The results are summed up in following table 3.
TABLE-US-00003 TABLE 3 Surface dosage Deep dosage (0.07 mm) (10 mm)
Technical staff Pelvis mSv (mrem) 0.027 (2.7) 0.003 (0.3) Eyes mSv
(mrem) 0.026 (2.6) 0.004 (0.4) Hands mSv (mrem) 0.35 (35) Medical
staff Pelvis mSv (mrem) 0.038 (3.8) 0.004 (0.4) Eyes mSv (mrem)
0.12 (12) 0.054 (5.4) Hands mSv (mrem) 0.35 (35)
[0090] In a non-limiting example, the production process of the
anti-tumoral compound according to the present invention comprises:
[0091] a preparation phase of a chemical fibrinogen and
aprotinin-based injectable compound; [0092] a preparation phase of
a chemical trombine and calcium chloride-based injectable compound;
[0093] a phase of pre-dosing of said chemical compounds, inside
special disposable syringes, and the subsequent low temperature
storage of the same; [0094] a warming phase of said compounds, when
they are to be used, up to the temperature of 37.degree. C.; [0095]
a first phase of adding said compounds carried out by means of a
solution of biocompatible microspheres, labelled with a high energy
isotope for therapeutic use, like the yttrium radioactive isotope
(.sup.90Y); [0096] a second phase of adding said compounds, carried
out by means of an epinephrine-based solution; [0097] an
administration phase of equivalent doses of said compounds,
determining the localized formation of a haemostatic gel comprising
above listed adding substances, carried out by means of a special
coaxial catheter with double lumen.
[0098] In a possible embodiment, the process for the production of
said anti-tumoral compound comprises: [0099] a preparation phase of
a chemical injectable compound consisting of a synthetic
polyethylene glycol and of a diluted solution of hydrochloric acid;
[0100] a preparation phase of a chemical injectable compound
consisting of a synthetic polyethylene glycol and of a solution of
sodium phosphate/sodium carbonate; [0101] a pre-dosing phase of
said chemical compounds inside special disposable syringes, and the
subsequent low temperature storage of the same; [0102] a warming
phase of said compounds at the moment of use up to the temperature
of 37.degree. C.; [0103] a first phase of adding said compounds,
carried out by means of a solution of biocompatible microspheres,
labelled with a high energy isotope for therapeutic use, like the
yttrium radioactive isotope (.sup.90Y); [0104] a second phase of
adding said compounds, carried out by means of an epinephrine-based
solution; [0105] an administration phase of equivalent doses of
said compounds, determining the localized formation of a hydrogel
comprising above mentioned adding substances, carried out by means
of a special coaxial catheter with double lumen.
[0106] As an alternative, the phase of adding the compounds, common
to both described procedures, and carried out with a solution of
biocompatible microspheres labelled with a high energy isotope for
therapeutic use, may be replaced by a phase of adding chemotherapy
drugs.
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